Eco-Epidemiology of Chagas Disease in Chile

There are four vector species of Chagas disease in Chile: Triatoma infestans, responsible for the domestic cycle; Mepraia spinolai, the main wild vector; and M. gajardoi and M. parapatrica, two coastal wild species whose importance as vectors is not well known. They are species of dry environments of the central-north region of Chile, whose best predictors of distribution are warm average temperatures and low rainfall. They are found in rock quarries, nests of birds, and small mammals, and T. infestans has sylvatic foci associated with a Bromeliaceae species. While human blood represents 70% of the diet of T. infestans, in M. spinolai this value is 7%, which means that a large part of Chagas disease in Chile is due to T. infestans. However, all species have high percentages of T. cruzi infection. Chagas disease in Chile follows the distribution of T. infestans, and although the cycle of domestic transmission by this vector is interrupted, there is still a constant prevalence and mortality and ascending incidences. Models predict that although climate change will not vary greatly the north-south distribution of vectors, it could increase the reproductive number of the disease, increasing risk areas of Chagas disease.


Introduction
American trypanosomiasis or Chagas disease is caused by the flagellated protozoan Trypanosoma cruzi, transmitted by several hematophagous insect species (Hemiptera, Reduviidae, and Triatominae) which in Chile are known as vinchucas. This protozoan species undergoes part of its development cycle (epimastigotes and trypomastigotes) in the insect vector, and when it ingests blood of a vertebrate host, the infectious trypomastigotes are eliminated with the in monkeys, he found a great quantity of flagellates, calling the new species Shyzotrypanum cruzi (today Trypanosoma cruzi) in honor of Dr. Oswaldo Cruz. Later, in 1909 he found a naturally infected cat and on April 14 found in the village of Santa Rita a 2-year-old girl named Berenice who lived in a house infested with P. megistus with a feverish condition and found in her blood the protozoan T. cruzi, describing the disease in 1909 [8]. Later, Carlos Chagas wrote about acute and chronic forms of the disease (1911) and the life cycle of T. cruzi (1931) [9], among other topics. in Chile [10].
Knowledge of this disease has been progressively increasing in Chile thanks to the contribution of numerous researchers. Schenone, in 1980, [11] recognized three stages in the investigation of this disease. In the first stage, from 1937 to 1943, research focused on detecting the disease and tried to determine the endemic areas, detecting vector species and reservoirs. Important studies in this stage included those of Drs. G. Gasic, V. Bertín, S. Massa, and R. Gajardo Tobar. In the second stage, from 1944 to 1952, there was a more systematic study, determining the magnitude of the problem and conducting systematic surveys to determine the epidemiology better. The remarkable work of Dr. Amador Neghme was published in this period. The third stage can be established from 1953 to 1994 where there was a fruitful work of many researchers who have helped to clarify clinical aspects, congenital transmission, blood banks, epidemiology, distribution of endemic areas, the reservoir, natural history, ecology, physiology, and behavior of vectors. In this stage, the contributions of Drs. H. Schenone, W. Apt, and A. Atías and their teams stand out in epidemiological and clinical aspects. The fourth stage subsequent to 1995 had been added in which the investigation has focused more on specifying aspects not revealed in the previous periods and that has been marked by the acknowledgment of the interruption of the home transmission chain by Triatoma infestans which occurred in 1999. Research was focused mainly on laboratory and diagnostic improvement, on congenital and transfusion treatment and transmission, and on the study of the ecology of Chagas disease vectors and T. cruzi. There were important improvements in the detection of the disease, the control of blood banks and the success of domiciliary disinfestation carried out by the vector control area of the Ministry of Health. A negative effect of the declaration of the interruption of the vector transmission chain has been less interesting and resources for the study and control of this disease contributes to perpetuate it as an unattended disease.

Eco-epidemiology of vectors
Four species of insect vectors of Chagas disease have been described in Chile. The species responsible for the domestic cycle is Triatoma infestans, and the species involved in the wild cycle are Mepraia spinolai (Figure 2), M. gajardoi, and M. parapatrica.

Distribution and niche
The vector T. infestans, a bug with characteristic yellow spots in the connexivum, has the widest distribution in Chile, between 18 and 34°S (Figure 3). It is found in domestic habitats, but foci of reproductive populations have also been detected in wild habitats [5][6][7]. In the domestic habitats, it is found in cracks of adobe walls or in "quincha" (wooden branches covered with mud), roofs of branches, and dwellings and chicken coops of the peridomiciliary zone.
In sylvatic habitats it has been found forming colonies associated with plants of Puya chilensis (Bromeliaceae).
Mepraia spinolai is a wild species endemic to Chile with high polymorphism, with apterous females, and apterous, winged, and brachypterous males with red spots in the connexivum [12][13][14]. It is found between 26 and 34°S, from the sea level to 3000 m (Figure 3) [11]. Their habitat is made up of rocky areas such as quarries and cracks, bird nests, and animal caves [15] and sometimes peridomiciliary pens and walls and in human dwellings [16,17].
Mepraia gajardoi is a coastal, wild species that lives between latitudes 18 and 26°S, feeding on small reptiles and mammals in the area. The males have generally blackish coloration with small reddish lateral spots in the dorsal part of connexivum. Male brachypterous and female micropterous.

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Mepraia parapatrica is a blackish species with red-orange spots in the connexivum, which only lives at 25°S. The females are micropterous, while the males are brachypterous and macropterous. It also lives on the coast, feeding on rodents and reptiles in the area.
Climate change predictions in Chile include an increase in temperature, with a gradient of higher to lower temperatures from north to south and from the Andes to the Pacific Ocean. During the 2011-2030 period, the temperature increase would be about 0.5°C in the southern  zone and 1.5°C for the north and the Chilean altiplano. A decrease in precipitation of 5-15% is expected during the same period. The distribution of T. infestans and Chagas disease is associated with maximum temperature and the precipitation during the driest month [18]; thus, the distribution of T. infestans would be little affected by climate change. This is consistent with the decrease in suitable areas proposed for M. spinolai in the same area and is in contrast to the high impact on the distribution of M. gajardoi, a species with a small distribution on the coast of northern Chile [19]. Under the assumption of niche conservatism, the latter species would suffer disappearance of its habitat, while M. spinolai, a species with distribution similar to T.
infestans from 25°S southward and with similar preferred environmental conditions, would decrease its distribution area in the interior valleys while increasing its distribution on the coast [19]. Since T. infestans is a species residing in arid and semiarid habitats, its distribution area would not be affected significantly. However, the transmission risk of Chagas disease in this zone could be increased because of changes in metabolism, survival, reproduction, biting rates, or densities of the insects.

Ecology and population dynamics
There are very few attempts to estimate the population density of vectors. A useful measure is the so-called triatomine index used for domestic vectors such as T. infestans, which is defined as the number of insects captured by a person in a house in 1 hour. Schenone estimated in these species indices of 54.5 for the Antofagasta Region in 1980, 19 [21]. The density per square meter has been estimated in this species between 15 and 364 vinchucas/m 2 , with an average of 79 vinchucas/m 2 in areas of rock walls in Colina [22]. This species can be found in high densities [22][23][24][25][26], even in mixed colonies with T. infestans, and has been found in human habitations [14,17,27,28]. For example, Schenone et al. [27] reported the presence of 288 specimens in 50 rural dwellings in regions III, IV, V, and Metropolitan. In this sense M. spinolai is a potentially dangerous species, especially in areas where the usual contact with humans occurs, as in quarry areas, and in some areas around Santiago where it is currently being urbanized, such as Colina, Lampa, and Til-Til. Also, from the perspective of its food sources, M. spinolai is in the phase of domiciliation [4,29,30], with 7.4% human blood in its diet [29,31].
Another approximation to get an idea of the density can be obtained from the number of specimens referred to the Institute of Public Health of Chile; these come in greater proportion from the regions of Antofagasta, Atacama, Coquimbo, Valparaiso, and Metropolitan (Santiago). A recent study [32] reported that 8331 triatomines have been received between 2005 and 2016. A 73.7% correspond to T. infestans, 24.0% to M. spinolai, and 2.3% to M. gajardoi. Their numbers increased over this period. This high proportion of T. infestans could be explained because this Just open this same document with Adobe Reader. If you do not have it, you can download it here. You can freely access the chapter at the Web Viewer here. species, once eliminated from human habitations, has been able to recolonize wild habitats with several foci whose magnitude has not been completely clarified. From the first description of a wild focus in Chile in 2006 [5] in Calera de Tango, and in Til-Til, the new outbreaks in Sahondé, Putaendo [6] to the reports of wild foci in the cities of Valparaiso 2009, Atacama 2014, and Coquimbo 2015 [7].
The data reported by the Ministry of Health show the proportion of infested dwellings (home infestation) in 1999 and annual data since 2010 and divide the information into the percentage of colonized houses, that is, colonies with evidence of active reproduction, the individual visits to houses that receive adult individuals but without colonization, and the total (the sum of both). Household infestation has clearly decreased in this period, but the proportion of houses with individual visitors has increased. Currently, domiciliary infestation is estimated at 0.05% [32].
The vinchucas in Chile are long-lived species, surviving around 18 months in the laboratory [12,13,24,33]. Their development is strongly affected by temperature and relative humidity like all triatomines [34]. The development of T. infestans completely ceases at temperatures below 16°C, and temperatures above 40°C are lethal [35]. The effect of relative humidity (RH) and its importance in molt periods has been discussed [36]. Combinations of variable ranges of low temperature and RH affect the maturation of T. infestans and M. spinolai ( Table 1). While at constant temperature and humidity, the pre-imago period consisting of five nymph states (N1-N5) is 6.1 months in T. infestans [37]; this increases to 14 environments [24,38,39]. In the main wild vector, M. spinolai, this period is between 9 and 10 months under constant conditions [12,33], while in environments with RH and T variability, only nymphs are obtained up to N5 status. With greater restriction at low temperature and humidity, they only reach the N2 status in 12 months [24]. The arrest of secondary development in unfavorable conditions (induced diapause) has been observed in both species [24,33,40]. Also, some parameters like the net reproductive rate (R 0 ) are strongly affected. Both species present survival curves with exponential decays and similar mortality rates [24,28,33,41]. The mortality and fertility rates in T. infestans present periodic variations during the year even under relatively constant environmental conditions. For example, under laboratory conditions the mean fecundity of T. infestans varied from 0.39 eggs/female/week in autumn to 1.63 eggs/female/week in spring, with maximum values of 7.59 eggs/female/week in spring and 5.83 eggs/female/week in summer. Maximum mean mortality and fertility rates were in spring and summer [42].

Ecophysiology and behavior
Triatoma infestans is a diurnal insect, while all species of the genus Mepraia are diurnal. In the laboratory M. spinolai moves between 15 and 42°C with a preferred temperature of 24.8°C [43]. T. infestans moves between 18 and 42°C with a preferred temperature of 24.2°C [43]. Other authors have found that T. infestans preferred temperatures between 26 and 27°C [44] and variations from 28 to 29°C at the beginning of the night, immediately after the ingestion of blood, but 25°C 12 days later [45,46]. The synchronization of activity patterns to the L/D cycle is similar to other triatomines [47][48][49][50][51]. Other activities synchronous to the L/D cycles are the rhythms of oviposition [52], molt [53], hatching [46], and aggregation [54]. The stimulus for orientation and approach to a potential prey is temperature, displaying the classic pattern of antennal movements-locomotor movement and extension of the proboscis [55,56]. T. infestans decreases the frequency of antennal movements when it is within 30 to 15 cm of its prey, whereas M. spinolai always maintains a low frequency, which may be due to a greater distance of perception in this species [57]. Once in contact with its prey, T. infestans introduces its proboscis, sucking blood, being able to increase its weight from four to six times in a single ingestion [38,39,57]. The volume of blood ingested is estimated between 30 and 70 ml when fed on a species such as Mesocricetus auratus [58]. The bite frequency in T. infestans has been estimated at 0.0754 bites/day [21]. The bite frequency of M. spinolai has been estimated at 0.155 bites/day, with volumes of blood ingestion between 20 and 160 mg. The intake volume has been found to be inversely correlated with the weight prior to intake, which is an indicator of nutritional status. Thus, the volume of the intake is related to the time elapsed since the last feeding and to the degree of distension of the abdomen [59].
T. infestans emits its dejections during the feeding act [60], which takes on average 19.5 min [38,39,57], usually between 3 and 4 min from the start of feeding, while in M. spinolai this latency is 24.4 min and not necessarily on the prey, which decreases the probability of transmission [38,39,57]. The bite rate and the latency between the start of the bite and the dejection are affected by the presence of the T. cruzi parasite in the vector; M. spinolai showed a higher frequency of bite and a lower latency of dejection in infected individuals [59].

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The feeding spectrum of T. infestans in Chile was obtained by means of ag-ac reactions and double gel diffusion [60]. The diet of this species is made up of humans 68.4%, cats 6.1%, dogs 3.2%, rabbits 5.9%, rodents 1.6%, Artiodactyla 0.3%, birds 7.2%, and amphibians 0.5%. The proportions for M. spinolai are humans 7.4%, cats 3.7%, dogs 12.3%, rabbits 53.1%, rodents 9.9%, Artiodactyla 12.3%, and birds 1.2% [29]. The amplitude of the trophic niche of M. spinolai is greater than that of T. infestans, and they have a niche overlap of 0.229 [29]. An increase in the amplitude of the niche in times of greater heat has also been demonstrated [29]. Introducing the information of the food profile of 15 species of triatomines with multivariate analysis techniques has shown a clear separation between species of domiciliary habits and peridomiciliary, wild, and stenophagous specialists; M. spinolai is among the peridomiciliary species [4]. In a later study, this species was located between wild and peridomiciliary [30]. The high trypano-triatomine indices in T. infestans are interesting, since a decrease of these indices was expected once these insects were removed from human habitats. Thus, for example, in Uruguay, the indices were drastically reduced as a result of vector control actions [61]. An explanation for the lack of a decline in these indices in Chile could be that despite the change in diet that involves the elimination of the human environment, T. infestans can find rodents and other species with high infection rates that make high trypano-triatomine indices persist. This may be true, since there is a great diversity of infected wild, domestic, and peridomestic mammals, some reaching levels of infection higher than 10% [15,62], but this is also probably true in Uruguay.

Trypanosoma cruzi lineages
Lineages of T. cruzi have been recognized for a long time. Initially, isoenzymes that differ in gel electrophoresis were classified as zymodemes Z1 and Z2, the first one mainly associated with the wild cycle and the second one with the domestic cycle [63]. Subsequently, biochemical and genetic differentiation was carried out, and two lineages, TcI corresponding to Z1 and TcII corresponding to Z2, were proposed. However, the first TcII was divided into five subgroups a, b, c, d, and e, where TcIIb corresponded to Z2, TcIIa to the new zymodeme Z3 and TcIIc, and d and e to hybrids [64]. Subsequently, subgroups were also recognized in TcI: a, b, c, and d [63,65]. Currently, it has been simplified into six subgroups, from TcI to TcVI, where TcI corresponds to Z1, TcII to TcIIb (Z2), TcIII to TcIIc, TcIV to TcIIa (Z3), TcV to TcIId, and TcVI to TcIIe.
It has been proposed that in small wild mammals TcI and TcII would be associated with marsupials and placental mammals, respectively. However, the TcI, TcII, TcV, and TcVI lineages have been detected in the rodent Octodon degus in Chile [26,70]. The same lineages have been detected in wild Oryctolagus cuniculus [71], and in 117 individuals of different infected species, TcI, TcII (TcIIb), TcV (TcIId), and TcVI (TcIIe) have been detected with frequencies of 38, 41, 26 and 9%, respectively, in wild mammals. In peridomestic mammals the frequencies of these lineages were 29, 33, 43, and 14%, respectively. More than one lineage was found in 31% of the individuals analyzed, without specific association with marsupials [72,73]. Thus, it seems that the information on the wild mammal reservoir and the vectors T. infestans and M. spinolai is quite consistent in pointing to TcI, TcII, TcV, and TcVI as the main circulating lineages, although more studies are still missing in the other wild vectors of the genus Mepraia.

Reservoir
The animal reservoir is very extensive; it is constituted by mammals of the peridomestic environment such as dogs, cats, goats, rabbits, sheep, horses, donkeys, and cattle, some carnivores, numerous rodents, and some small marsupials. Infection in mammals by T. cruzi has been described in around 150 species in America [74] and is widespread in numerous orders; the most important reservoirs are dogs, cats, and goats, due both to high infection rates and to their mobility which establishes a bridge between domestic and wild cycles. Proportions of infection by T. cruzi have been reported 14.5% in dogs, 10.7% in cats, 9.4% in goats, 12.1% in rabbits, and 4.8% in sheep [75]. Current studies with PCR in wild mammals have reported percentages of infection between 26 and 59% in the species Capra hircus (goat), Thylamys elegans (marsupial), O. degus, Phyllotis darwini, and Abrothrix olivaceus (rodents) [72] and large increases in interannual infection rates from 300-400%, which could be explained by a delayed response to the El Niño weather phenomenon after the emergence of small rodents [25].

Distribution of the disease
Chagas disease extends in America from the Southern United States at parallel 35°N to southern South America at parallel 34°S on the Chilean side and 45°S on the Argentine side. In this zone, 21 countries report active transmission, with current prevalence very difficult to assess since most of the studies refer to the prevalence in endemic rural areas [15]. The median prevalence in these areas is approximately 8.15%. The lower extreme values probably represent Chagas disease in controlled or urban areas and the maximum Chagas disease prevalence in hyperendemic areas without protection of health systems. Currently, emergence of Chagas disease in Europe has been reported through immigrants and subsequent congenital Just open this same document with Adobe Reader. If you do not have it, you can download it here. You can freely access the chapter at the Web Viewer here.
transmission. For example, Basile et al. [76] reported more than 4000 cases diagnosed in different countries, with the highest number of cases in Spain, but Strasen et al. [77] proposed around 95% underreporting. These latter authors indicated that there could be between 14,000 and 180,000 cases in this continent.
In Chile, Chagas disease is distributed between the Arica and Parinacota Region (18°30'S) and the O'Higgins Region (34°36'S) (Figure 4), coinciding in large part with the distribution of the vector domestic T. infestans [18]. The highest incidence rates are recorded between Antofagasta and Coquimbo, with Antofagasta, Coquimbo, and Metropolitan Regions concentrating approximately two-thirds of the reported cases ( Table 2). Please use Adobe Acrobat Reader to read this book chapter for free. Just open this same document with Adobe Reader. If you do not have it, you can download it here. You can freely access the chapter at the Web Viewer here.

Prevalence and incidence
Chagas disease is one of the main neglected diseases that affects the Americas and has now become an emerging disease in some parts of America and Europe [78][79][80][81], which has even been compared to the early stage of the HIV/AIDS epidemic [79]. The annual incidence varies between 28,000 and 56,000 people and between 10,000 and 14,000 deaths per year [79], affecting 6-11 million individuals [82] with 65-100 million people at risk in the world [78][79][80]83]. The population at risk in Chile is 873,415 people [80, 81]. The latest national health survey (ENS) reports a prevalence of T. cruzi infection of 0.7% of the population, with a prevalence of 1.5% in rural areas and 0.6% in urban areas [81], and ministerial reports indicate that home infestation by T. infestans is practically nonexistent [80], which contrasts sharply with the data reported in the 1980s and 1990s. For example, between 1937 and 1980, a general prevalence of 16.7% was reported in endemic areas, with a maximum of 43.6% in the Coquimbo Region [11], which did not vary significantly between 1982 and 1985 [84], whereas between 1982 and1989 differences were already reported between rural areas with prevalence of 16.7% and urban areas with prevalence of 1.9% [16]. The same occurs with domiciliary infestation, in which previous reports indicated infestations between 26.8 and 33.2% of dwellings in endemic areas between Arica and the O'Higgins Regions [11,80].
A study covering 60 years of the disease in Chile of patients referred to the University of Chile and studied through xenodiagnosis revealed an average prevalence of 9.35 ± 0.1% [32]. This prevalence value of 9.35% should be considered as the level for highly endemic zones. It is in the range between 8 and 12% reported by , also based on xenodiagnosis, and is similar to the estimated value for Latin America. This value does not present any variation in the 65 years of study, regardless of the changes in the health systems or interruption of the chain of transmission. Accurate estimation of the prevalence of Chagas disease is a difficult task since it depends not only on the sampling characteristics (random, stratified, etc.), sample size, and bias but also on the screening method used, which in the case of Chagas disease can be by xenodiagnosis, ELISA, immunofluorescence, and/or Western blot.
The values reported by the 2009-2010 ENS based on 4650 volunteers using IgG ELISA show 0.7% average prevalence, with 1.5% in the rural population and 0.6% in the urban population. These values are surprisingly similar to those reported for the urban population in 1982-1989 [85]. In this sense, the prevalence shows an evolution toward the values of an urbanized population.
The incidence in Chile shows a progressive rise from 1985 onward (Figure 5)   per 100,000 inhabitants [32], staying relatively stable. One explanation for this temporal dynamics is that the progressive increase was not explained by a particular milestone but by a progressive improvement in the notification attributable to better staff preparation and a better notification system. Another possibility that cannot be ruled out is that this increase is real, and in this case, it should have an impact on mortality rates in the long run, a fact that is not yet evident. If the relative stability detected since 2009 persists, it would indicate that it would be reaching an adequate estimation of the endemic equilibrium, as the models predict [23,86].
Mortality shows stability over the years (Figure 5). The average mortality rate is 0.36 ± 0.55 per 100,000 inhabitants [32]. Chagas disease affects the entire population in Chile, especially people of working age, with the highest rates between 30 and 65 years of age (Figure 6) [81].

Transfusion and congenital Chagas disease
The seroprevalence of T. cruzi in blood donors has been studied in Chile since the 1960s, with a national average of 3.7% reported between 1962 and 1988 [15]. Subsequently, this value has decreased; it was estimated between 0.5 and 1.6% according to information from the ISP between 2000 and 2005, estimated with the ELISA IgG method, and confirmed with IFI [87].
Currently, the seroprevalence of T. cruzi in blood donors is estimated at approximately 0.6%. The latest studies in the blood bank of the Clinical Hospital of the University of Chile were 0.4% positive out of a total of 24,568 [87].

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A meta-analytic study that considered 13 case studies and 51 observational studies in ten countries estimated the rate of congenital infection was 4.7% with a CI of 3.4-5.7%. This means that in a population of mothers infected with T. cruzi, 4.7% of newborns are congenitally infected [88]. In this study it is proposed that in endemic areas the rate is 5% in endemic countries but lower in non-endemic countries (2.7%) and proposes a rate of 2.5% for Chile. In the same year, in a study conducted in Choapa, a highly endemic area, this rate was estimated at 4.7% [89].

The reproductive number (R 0 )
The transmission of Chagas disease depends mainly on vector and congenital transmission. Accidental and transfusion transmissions are very rare and oral transmission only occurs in particular areas where the contact between man and nature is very close. The reproductive number of an infectious disease (R 0 ) corresponds to the average number of secondary infections produced by an infected individual. Thus, if R 0 is greater than 1, the disease is established in the population, and if R 0 is less than 1, the disease disappears. In the case of Chagas disease, the main component of the reproductive number is given by vector transmission, and when this is cut off, congenital transmission alone is incapable of perpetuating the disease [86,90]. There are very few attempts to estimate the R 0 of this disease, an exception being the study by Massad [91], who estimated it at R 0 = 1.25 for a region of Brazil. Other estimates based on plausible approximations of many parameters obtained values of R 0 = 7 in Colombia [92] and R 0 = 2.86 [23] and R 0 = 1.52 in Chile [86]. However, recently in a spatial approach, a median value of R 0 = 1.02 has been proposed, with an approximate spatial variability between 0 and 5. The reproductive number could vary in different climate change scenarios as consequence of changes in entomological parameters such as biting rate, density, and mortality rate, increasing the Chagas risk area between 13 and 18% [93].

Conclusion and the way forward
Chile is in a privileged situation. It has only one domestic vector and probably only one wild vector of epidemiological importance, and the chain of domestic vector transmission by T. infestans is cut off. The wild reservoir is made up of small rodents, and the circulating lineages of T. cruzi are similar to the rest of America. However, there are some problems that persist: (1) The peri-anthropic reservoir is diverse and has bridging animals between the wild and domestic cycles that facilitate the spread of Chagas disease, such as dogs and goats; (2) housing and education conditions in Northern Chile are limited; (3) there are no control or education campaigns on wild vectors, and human dwellings are built on their territory. In addition there are wild foci of T. infestans and vector home intrusion; (4) prevalence, incidence, and trypano-triatomine indices still do not decrease; and (5) climate could change the epidemiological situation.
Given the obvious opportunity to eradicate Chagas disease in two generations, as predicted by the models, the way forward should be focused on (1) strengthening education campaigns of the population; (2) strengthening the monitoring of housing and peridomestic animals; (3) detection, study, and control of wild foci; and (4) reinforcing the study of the effect of climate change on the epidemiology of Chagas disease.